Venous Thromboembolism

(VTE) in Pregnancy

Lee Lai Heng

Haematology

Singapore General Hospital

Pathogenesis of VTE in PregnancyVirchow’s triad of factors underlying VTE all occur in pregnancy

Hypercoagulability

Endothelial Damage

Venous Stasis

•Increase Fibrin generation

•Decrease fibrinolytic activity

•Increase II, VII, VIII, X

•Decrease free protein S levels

•Acquired APCR

•Progesterone-mediated

increases in venous

distensibility cause an

increase in venous stasis.

Reduction in venous flow

velocity up to 50% occurs in

the legs by 3rd trimester and

lasts until approximately 6

weeks after delivery

Endothelial damage to pelvic vessels can occur secondary to compression of the inferior vena cava

and iliac veins by the pregnant uterus and resulting stasis or during vaginal or abdominal delivery

THROMBOEMBOLISM IN O&G

VTE risks is 5-6 X higher in pregnant women

compared to non pregnant women

PE in 24% of untreated VTE and 15% of PE fatal

Major cause of marternal morbidity and mortality

17% maternal deaths in western world

VTE in Pregnancy

2/3 of VTEs occurred in the antepartum period and

distributed equally among 3 trimesters

Risk of postpartum VTE is about 3X that of antenatal

VTE

43 - 60% of PE appear to occur in the puerperium.

Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk

and leg of presentation. Obstet Gynecol Surv 1999;54:265-71.

Venous thromboembolism in pregnancy and the puerperium: incidence and additional risk factors

from a London perinatal database. BJOG 2001;108:56-60.

Thrombosis during pregnancy and the postpartum period. Am J Obstet Gynecol 2005;193:216-9.

Risk factors for pregnancy associated venous thromboembolism. ThrombHaemost 1997,78:1183-8

R Iliac artery compressing

on L Iliac Vein

Almost 90% of DVTs occur on the LEFT side in pregnant women

compared with 55% among women who are not pregnant

Lancet 1999;353:1258– 65

Thromb Haemost 1992;67:519–20

Incidence of VTE in Pregnancy

Estimated at 0.76 to 1.72 per 1000 pregnancies

4X the risk in the non-pregnant population

Incidence in Asia Unknown

Trends in the incidence of venous thromboembolism during pregnancy or postpartum:

a 30-year population-based study. Ann Intern Med 2005;143:697-706.

Venous thromboembolism during pregnancy and the postpartum period: incidence,

risk factors, and mortality. Am J Obstet Gynecol 2006;194:1311-5

Venous Thromboembolism in ASIA Perceived as rare in Orientals / Asians

Perception re-inforced

Absence of Factor V leiden in Orientals

Absence of Prothrombin 20210 in Orientals

Increasing trend in DVT prevalence

among hospitalised patients noted

0.453% (2002-2003)

0.158% (1996–1997)

0.079% (1989–1990)

Absence of Pulmonary Embolism in Asians Br Med J 1964

The Rarity of Pulmonary Thromboembolism in Asians. Singapore Med J. 1968

Trends in prevalence of VTE…. Ng HJ, Lee LH. Thromb Haemost 2009; 101: 1095–1099

Maternal VTE- Hong Kong

January 1998 to December 2000

32 women diagnosed with VTE (80% calve DVT, 2 PE, 1 died)

Incidence of 1.88 per 1000 deliveries (total 16,993 deliveries)

Western incidence of VTE ranges from 0.6 to 1.3 episodes per 1,000

deliveries

Increase in U/S request and VTE diagnosed

Doppler US requests for suspected DVT before and after the event of

maternal death were 1.62 and 10.7 per 1000 deliveries (P <.001);

Corresponding cases of deep venous thrombosis diagnosed were 0.29

and 2.94 per 1000 deliveries, respectively (P <0.001)

Venous thromboembolism in pregnant Chinese women Obstet Gynecol. 2001 Sep;98(3):471-5

8th ACCP, Chest June 2008

Maternal Mortality - Singapore

Chen LH 1997 - maternal deaths (92-95)

3/7 die from PE.

4.9 per 100 000 maternities

Maternal Mortality 1990 to 1999 (Lau G 2002 )

51 cases of maternal deaths

Amniotic fluid embolism -16 deaths (rate 3.3 per 10,000 life births)

Massive Pulmonary embolism - 10 deaths (2.1 per 10,000 life births)

Chen LH et al- 3 cases of fatal pulmonary embolism in obstetrics. Ann Acad Med Singapore. 1997 May;26(3):356-9

Loh FH, Arulkumaran S, Montan S, Ratnam SS.- Maternal mortality: evolving trends. Asia Oceania J Obstet

Gynaecol. 1994 Sep;20(3):301-4.

G Lau. - Are maternal deaths on the ascent in Singapore? A review of maternal mortality as reflected by coronial

casework from 1990 to 1999. Ann Acad Med Singapore. 2002 May;31(3):261-75.

Reduction of Maternal mortality from PE

Prophylaxis of those with increased risks for VTE

Aggressive investigations in those with suspected

VTE to facilitate early treatment

Evidence for VTE prevention strategies and anticoagulant

regimes based limited data from pregnant subjects and often

extrapolated from non-pregnant subjects

VTE Prophylaxis – Risk Stratified Approach

AETIOLOGICAL RISK FACTORS

Age >38 years,

Para 4 or more

Obesity

Pre-eclampsia

Hospitalization and restricted activity

Method of delivery - emergency LSCS

Extended major surgery - Caesarean hysterectomy, LSCS plus ovarian cystectomy

Past history of deep vein thrombosis or pulmonary embolism

Lupus-anticoagulant-associated thrombotic disease

Hereditary thrombotic diseases

PC, PS, AT deficiencies

Hyperhomocyteinaemia from MTHFR mutation

Prothrombin G20210A, Factor V Leiden

RCOG Green-top Guideline

No. 37 2009

RCOG Green-top

Guideline No. 37 2009

VTE Prophylaxis – Previous VTE and Thrombophilia

RCOG Green-top Guideline No. 37 2009

Thrombophilia and VTE in Pregnancy

Presence of thrombophilia in pregnancy (a hypercoagulable

state ) does not always result in VTE

•About 50% of cases of VTE in pregnancy assoc with thrombophilia

•Inherited thrombophilias are common, affecting 15% of Western populations

•VTE occurs in only 0.1% of pregnancies

•Routine screening of pregnant women is not cost-effective

Venous thrombosis: a multicausal disease. Lancet 1999;353: 1167-73.

Screening for thrombophilia in high-risk situations: a meta-analysis and cost-

effectiveness analysis. Br J Haematol 2005;131: 80-90.

Thromboembolism Prophylaxis

Thrombotic risk assessment

Thromboprophylaxis initiated

according to risk stratification

Each patient considered individually

Guidelines on Treatment and Prophylaxis

Diagnosis of VTE in Pregnancy

•Very challenging

•Classic s/s of VTE e.g. Leg swelling, tachycardia, tachypnea,

and dyspnea, may be associated with a normal pregnancy.

•Common strategies and clinical score systems for DVT

pulmonary embolus have not been validated in pregnancy

•Sudden death can occur in pregnant patients with VTE

•Clinical suspicion is critical for the diagnosis of VTE - All

pregnant women with signs and symptoms suggestive of VTE

should be investigated quickly

DIAGNOSIS OF DVT

Clinical

Venography

Radiation hazard, can shield fetus with abdominal apron

Invasive

Doppler U/S - 95% sensitive in proximal DVT

Obesity, severe edema can limit the examination

MRI (Magnetic resonance imaging)

Does not involve radiation exposure

Is Gadolinium harmful to the fetus ?

High sensitivity and specificity for diagnosis of iliac-vein thrombosis

DIAGNOSIS OF PULMONARY EMBOLISM

Clinical, ECG, CXR - Unreliable

VQ lung scan, Spiral CT Pulmonary angiography a/w radiation

hazards

Fetal dose of radiation

VQ lung scan higher (640 - 800 μGy ) than CT (3 -131 μGy)

perfusion scanning alone will reduce the radiation exposure

VQ scan carries a slightly higher risk of childhood cancer in

offspring than does CTPA (1 case in 280,000 vs <1 in 1 million)

Maternal Radiation

higher with CT than with VQ (2.2 to 6.0 mSv vs. 1.4 mSv)

CT has greater risk of maternal breast cancer (the lifetime risk is

up to13% greater with CTPA than with VQ scans)

Radiation Risks and Pregnancy

Radiation exposure to the fetus from CTPA and lung

ventilation–perfusion scanning is negligible.

Reaching the exposure limit of 50,000 μGy, acceptable by

National Council on Radiation Protection and Measurements in

pregnancy, would require 100 ventilation–perfusion scans or

nearly 400 CTPAs.

PE during pregnancy is a serious condition and the risk of not

diagnosing a PE is much greater than the radiation risks

.

Pulmonary embolism in pregnant patients:fetal radiation dose with helical CT. Radiology

2002;224:487-92.

D- Dimer

Elisa method more sensitive than latex agglutination

Elevated in acute DVT

Also elevated in DIVC, trauma, malignancy, liver disease

Low positive predictive value - non specific

Used as a tool for exclusion.

Negative predictive values > 95%

Degradation product of cross linked fibrin blood clot

D-Dimers in Pregnancy

•Levels of d-dimer increase with the progression of a normal pregnancy.

•A study using a highly sensitive assay, (SimpliRED assay)

• Negative test in 1st and 2nd trimesters had a negative predictive value of 100%

(sensitivity and specificity of a +ve test were 100% and 60%,)

• Useful in pregnancy because a normal result excludes DVT and occurs frequently

enough to be clinically helpful.

• BUT not validated in larger cohorts of pregnant patients

•Has been shown that negative d-dimer test may not necessarily rule out VTE

•D-dimer test should be used in combination with other tests

Diagnosing pulmonary embolism in pregnancy: is there a role for D-dimer as a stand-alone test?

Crit Care Med 2006;34:2701-2.

A red blood cell agglutination D-dimer test to exclude deep venous thrombosis in pregnancy.

Ann Intern Med 2007;147:165-70.

Diagnosis of

VTE in

Pregnancy

N Engl J Med 2008;359:2025-33

TREATMENT of VTE

Objectives

Prevent local extension of thrombus

Prevent embolisation

Prevent recurrent thrombosis

DVT and PE are different ends of spectrum of a

single disorder. Similar Pharmacologic Treatment

TREATMENT of VTE

Anticoagulation is the cornerstone of treatment

Anti-thrombin replacement

In anti-thrombin deficiency, if levels <50% of normal

Replace with anti-thrombin concentrate at 50-70 iu/kg eod for 1 week after delivery

IVC filter - not recommended in pregnancy

Thrombolytic therapy - not recommended in pregnancy

Emergency embolectomy - for massive PE

Anticoagulation for new DVT

Immediate heparinisation at therapeutic dose

UFH to maintain PTT at 2X normal

LMWH to achieve anti-Xa levels of 0.6 to 1.2 U/ml

Importance of adequate anticoagulation

24% Untreated DVT develop PE

10 -15 X increase in recurrences if inadequately treated

Duration of Anticoagulation for new DVT

Maintain at therapeutic dose for at least 6 months after VTE

If patient is still pregnant after 6 months of therapeutic

anticoagulation, the doses may be decreased to

prophylactic doses

Warfarin may be used in the 2nd trimester if unable to

continue injections

Risks of CNS defects and intrauterine bleed bleeding

Prophylaxis till 6 weeks post partum

Complications of Anticoagulants during Pregnancy

Fetal Complications

Teratogenicity

Bleeding

Maternal Complications

HIT

Heparin Induced Osteoporosis

Bleeding

Anticoagulation drugs

Standard Heparin

Low Molecular Weight Heparin

Warfarin

Warfarin

Vitamin K antagonist

Oral preparation

Unpredictable absorption

Multiple drug interactions

Require frequent blood tests

Challenges in Warfarin Manangement during Pregnancy

Crosses the placenta

Increased foetal loss

Teratogenic in 1st trimester

Neurological malformations in any trimester

nasal hypoplasia

stippled epiphyses

CNS - ageneisi of corpus callosum, ventral midline dysplasia, optic atrophy

Fetal bleeding and retroplacental haemorrhage in last trimester

Post partum haemorrhage

Warfarin safe for foetus ?

True incidence of teratogenicity adverse affects not

known

Previously reported cases associated with high dose

warfarin

Lower dose in moderate intensity anticoagulation

probably safe at 0-6 weeks conception and during

second trimester

Sharouni et al; British Heart Journal 1994

Foetal Warfarin Syndrome

Occurred in 1997, Neonatology SGH

Mother on warfarin 3.0-3.5 mg daily for mitral valve

replacement from conception to 36 weeks

Singapore Paediatric journal. March 2000

J Med Assoc Thai. 2005 Nov;88 Suppl 8:S246-50.

Fetal warfarin syndrome.Sathienkijkanchai A, Wasant P.

Division of Medical Genetics, Department of Pediatrics, Faculty of Medicine, Siriraj Hospital, Mahidol

University, Bangkok, Thailand.Abstract

Fetuses exposed to Warfarin in the first trimester of pregnancy have an increased risk of embryopathy which consists

of nasal hypoplasia and stippled epiphyses, known as fetal warfarin syndrome or warfarin embryopathy. We herein

report a first case of an infant with fetal warfarin syndrome in Thailand. The patient was an offspring of a 34-year-old

mother with history of SLE and arterial embolism for several years. She had an unplanned pregnancy while taking

warfarin. The patient developed difficulty breathing in the first few hours after birth from severe nasal hypoplasia. He

also had short limbs, brachydactyly, nail hypoplasia, and calcifications in the epiphyseal regions of humeri, femora and

vertebrae radiographically. The patient eventually died from respiratory failure at 6 months of age.

Standard Heparin

Safe for fetus

Maternal complications

2% Bleeding in pregnant patients

Increased bleeding/thrombotic complications

unpredictable bioavailibility,unstable anticoagulation profile

Osteoporosis ( heparin >1 month)

30% significant reduction in bone density

2-3% vertebrae fractures

HIT Thromb Haemost 1996; 75: 254-257

N Engl J Med 1995; 332:1330-1335

Low Molecular Weight Heparin

Predictable bioavailability & long half-life

Constant and adequate anticoagulation profile

Convenient & easy administration

Does not cross the placenta

No adverse report of its use in pregnancy

No significant osteoporosis reported in long term use

Lower incidence of thrombocytopenia

Anticoagulant of choice during pregnancy

Choice of Anticoagulation

Discuss with patients

Indications for treatment

Risks of embryopathy

Risks of thrombosis

Risks of bleeding

Informed Choice

Intra-partum Management - Patients on therapeutic

anticoagulation

Special caution must be excercised during labour and delivery

Admit for planned delivery when the cervix is favourable

Omit LMWH on the day of delivery

At induction of labour, start I/v unfractionated heparin if the

thrombotic risk is high

Stop i/v heprain once active labour begins

No active anticoagulation is recommended during delivery

Resume LMWH within 12 hrs after delivery (NO significant

bleed)

Overlap with warfarin till therapeutic INR achieved

Epidural Anaesthesia

Decision made on individual basis

Reports of spinal haematomas

Successful use in 43 pregnancies without complications

Safe if PTT normal and no standard heparin for 4-6 hours prior to

epidural catheter insertion

Can be given at least 12 hours after the last prophylactic dose and

24 hours after the last therapeutic dose of LMWH

LMWH can be re-started 3 hours after removal of epidural catheter

Peri-partum Bleeding

Exclude obstetric complications predisposing to

haemorrhage

Heparin and LMWH if present can be reversed with

protamine sulphate

Caesarian Section

Indications for Obsterterics Reasons only

Elective LSCS

stop infusional heparin at least 4 hours

before surgery

Emergency LSCS

consider protamine sulphate

Post Partum

Prophylaxis - anticoagulation should remain for at least 6 weeks

Therapeutic - the patient should continue with therapeutic

intensity of anticoagulation until 6 months after the thrombotic

event.

Unfractionated heparin, LMWH and Warfarin are safe for breast

feeding mothers

Warfarin which can be taken orally is usually the preferred

anticoagulation drug after delivery

Use of Anticoaglants in Nursing Mothers

Heparin and LMWH not secreted into breast milk

Warfarin does not induce an anticoagulant effect in

the breast-fed infant while the mother is on warfarin

treatment

LMWHs fot thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic

review of safety and efficacy. Ian A Greer, Catherine Nelson-Piercy. Blood 2005, 106: 401-407

May mothers given warfarin breastfeed infants ? Orne LE et al, BMJ 1977; 1: 1564-1565

Is warfarin sodium cotraindicated in the lactating mother ? McKenna R et al, J Pediatr 1983; 103: 325-327

For lactating women using warfarin or UFH who wish to breastfeed,

recommend continuing these medications

(Grade 1A) 8th ACCP 2008

Thank You